Investigating miR-125b target gene Arid3a in trisomy 21-associated leukemogenesis

Myeloid leukemia associated with Down syndrom (ML-DS) is characterized by the triad of fetal origin, trisomy 21 and truncating Gata1 mutations. Chromosome 21-encoded microRNAs of the miR-99a~125b tricistron are highly upregulated in ML-DS. We identified miR-125b as the dominant microRNA within this cluster synergizing with Gata1s during leukemogenesis. Combining RNA-sequencing with an shRNA-based positive selection screening in fetal hematopoietic stem/progenitor cells, we identified Arid3a as the main target of miR-125b, responsible for the oncogenic phenotype. While downregulating Arid3a lead to increased proliferation, restored expression of ARID3A in miR-125b high expressing human cell lines as well as patient-derived-xenografts impaired proliferation. Moreover, low ARID3A expression is associated with poorer overall survival in pediatric AML patients. Mapping the Arid3a protein interaction network, chromatin occupancy and transcriptional activity revealed its downregulation as a crucial event in pathogenesis of ML-DS. Hence, we established a novel role of transcription factor ARID3A as miR-125b target involved in myeloid malignancies.

Publication History

Article published online:
13 May 2020